2 alpha-methyl-9 alpha-fluoro-11 beta-17 alpha-dihydroxy-4-pregnene-3, 20-dione 17-acylates



United States Patent 2,992,244 2ot-METHYL-9a-FLUORO-11j3-17a DHTYDROXY-4- PREGNENE-SJG DIONE 17-ACYLATES John A. Hogg, Charleston Township, Kalamazoo County,

Frank H. Lincoln, Kalamazoo, and William P. Schneider, Kalamazoo Township, Kalamazoo County, Mich., assiguors to The Upjohn Company, Kalamazoo, Mich.,

a corporation of Delaware No Drawing. Filed Dec. 14, 1959, Ser. No. 859,097 2 Claims. (Cl. 260-39745) This invention relates to novel steroid esters and more particularly to 2a-methyl-9a-fluoro-11,B,17t-dihydroxy-4- pregnene-3,20-dione 17-acylates and to a process for the preparation thereof.

The novel 2u-methyl-9u-fluoro-l15,17ot-dihydroxy-4- pregnene-3,20-dione 17-acylates of this invention are highly active oral progestational agents with accompanying high degree of antidnfiammatory activity. Another advantage of the compounds of this invention is their very low mineralocorticoid activity.

The novel compounds of this invention can be prepared and administered to birds and mammals (including humans) in a wide variety of oral or parenteral dosage forms singly, or in admixture with other coacting coma pounds. They can be associated with a pharmaceutical carrier which can be a solid material or a liquid in which the compound is dissolved, dispersed or suspended. The solid compositions can take the form of tablets, powders, capsules, pills or the like, preferably in unit dosage forms for simple administration or precise dosages. The liquid compositions can take the form of solutions, emulsions, suspensions, syrups or elixirs. The novel compounds can also be administered topically in the form of o'intments, creams, lotions, and the like, with or without coacting antibiotics, germicides or other materials forming advantageous compositions therewith.

Ten thousand tablets for oral use, each containing 5 mg. of steroid are prepared from the following types and amounts of material:

The finely powdered steroid and lactose are mixed well and granulated with syrup starch paste. Starch and calciurn stearate are used as lubricants in the compressing step.

The oral administration of 1 tablet daily is useful in the treatment of severe functional uterine bleeding in humans.

The process of this invention comprises: epoxidation of 2a-methyl-9a-bromo-11,8,17u-dihydroxy-4-pregnene-3, 2 0-dione 17-acylate to give the corresponding Zia-methyl- 17a-hydroxy-9B,1lB-epoxy-4-pregnene-3,ZO-dione 17-acyl ate and fluorination of the 9,11-epoxy compound thus obtained with a source of hydrogen fluoride to give the corresponding 2oz methyl 90: fluoro-11B,17a-dihydroxy-4 pregnene-3,20-dione 17-acylate.

The novel compounds of this invention and the process ice for their preparation are illustratively represented by the following reaction scheme:

wherein Ac is the acyl radical of an organic carboxylic acid, preferably a hydrocarbon carboxylic acid containing from lto 12 carbon atoms, inclusive.

The starting steroids for the compounds and process of invention are 2a-methyl-9a-brorno-11fi,17a.-dihydroxy-4pregnene3,20-dione 17-acylates which are prepared in accordance with the procedures of Preparations 1 through 3 containing therein. The starting material for Preparation 1 is prepared in accordance with the preparations and examples of US. Patent 2,865,935, par ticularly Example 5, to give 2a-methyl-11 fi,17a-di-hydroxy-4-pregnene-3,20-dione.

In carrying out the process of invention, the 2mmethy-l 90c bromo 11,13,170: dihydro-x'y 4 pregnene- 3,20 dione 17-acylates are converted to the respective 2amethyl 9oz fluoro 1113,17 dihydroxy 4 pregnene- 3,20-dione 17-acylates in accordance with methods well known in the art, e.g., US. Patent 2,852,511 or US. Patent 2,838,498. The selected 2a-methyl-9a-bromo-11fl, 17a dihydroxy-4pregnene-3,ZO-dione 17-acylate is epoxidized with a mild base, potassium acetate is preferred, to give the corresponding 2a-methy-l-9fi,1lfl-epoxy-4-pregnone-3,20-dione 17-acy1ate. The selected 9,1l-epoxy compound thus obtained is then fluorinated with a source of hydrogen fluoride to give the corresponding 2a-methyl-9afluoro 1118,1711: dihydroxy 4 pregnene-3,20-dione l7- acylate.

The following preparations and examples are illustrative of the process and products of this invention.

PREPARATION 1 2oz-methyl-17ot-hydr0xy-4,9 (11 )-pregnadiene-3,20-dione A solution containing 3.60 g. of Za-mfi'fhYl-llfifl7u-dihydroxy-4-pregnene-3,20-dione in ml. of pyridine at 25 C. was treated with 2.21 g. of N-bromoacetamide.

Afiter 20 minutes the solution was cooled and an excess 3 of anhydrous sulfur dioxide was added with stirring. The

reaction mixture was kept at about 25 C. for a period ofv 30 minutes and then cooled. 100 ml. of water was then added with stirring to the cooled reaction mixture and the cooling was continued for several hours keeping the temperature at C. The precipitate thus obtained was collected on a filter, washed with water and dried under vacuum at 70 C. to give 2.9 g. of 2a-rnethyl-l7a-hydroxy- 4,9(11)-pregnadiene-3,20-dione. The crude product thus obtained was dissolved in a mixture of 50 ml. of methylene chloride and 25 ml. of Skellysolve B hexanes and chromatographed on a column containing 150 g. of Florisil synthetic magnesium silicate. The column was eluted with 160 ml. fractions of 8 percent acetone in Skellysolve B hexanes. Fractions 3-13 were combined to give 1.52 g. of product, which on recrystallization from acetonezSkellysolve B hexanes gave 0.93 g. of Zea-methyll7rr-hydroxy-4,9 (11 1)-pregrradiene-3 ,20 dione melting at 229231 C., [a] +92 (chloroform).

Analysis.-Calcd. for C H O C, 77.15; H, 8.83. Found: C, 77.85; H, 8.79.

PREPARATION 2 Za-methyZ-I 7a-hydroxy-4,9 (1 1 )-pregnadiene- 3,20-dione 17-acetate A mixture was prepared containing 1.0 g. of Zea-methyl- 17a-hydroxy-4,9(ll)-pregnadiene-3,20-dione, 20 m1. of acetic acid, 5 ml. of acetic anhydride and 0.4 g. of ptoluenesulfonic acid monohydrate. The mixture was stirred until a clear solution was obtained. The reaction mixture was allowed to stand for an additional period of several hours and was then poured into 96 ml. of water. The aqueous mixture was chilled at 5 C. until a precipitate was obtained. The precipitate was collected on a filter and washed with cold water. The precipitate was 4 PREPARATION 3 2u-methyl-9a-bromo-11 8,17a=dihydroxy-4-pregnene- 3,20-dione 17-acetate To a solution of 4.40 g. of 2a-methyl-l7u-hydroxy-4,9- (11)-pregnadiene-3,20-dione 17-acetate in 250 ml. of tbutyl alcohol and 50 ml. of methylene chloride was added a solution of 12.5 ml. of 70 percent perchloric acid in 87 ml. of water followed by a solution of 1.88 g. of N- bromoacetamide in 50 ml. of t-butyl alcohol. After stirring the reaction mixture for a period of about 15 minutes, a solution of 2.5 g. of sodium sulfite in ml. of water was added and the reaction mixture was carefully concentrated to about 440 ml. under reduced pressure with no external heat. The concentrate was stirred and 500 ml. of water was added to give 5.80 g. of Za-methyl-Qubromo 11p,17a dihydroxy-4-pregnene-3,20-dione 17-acetate as a yellow crystalline solid melting at 168170 C. An analytical sample was prepared by recrystallizing 0.5 g. of the yellow crystalline solid from a mixture of methylene chloride and Skellysolve B hexanes to give 0.4 g. of 2a-methyl-9a-bromo-11fl,17u-dihydroxy-4-pregnene-3,20-dione 17-acetate melting at 170172 C. with decomposition.

An,alysis.-Calcd. for C H BrO Br, 16.60. Found: Br, 16.60.

In the same manner substituting another Zea-methyl- 17u hydroxy 4,9(11)-pregnadiene-3,20-dione l7-acylate wherein the acyl radical is that of an acid listed in Prepanation 2, above, for Zea-methyl-17a-hydroxy-4,9(11)pregnadi'ene-3,20-dione 17-acetate in the procedure of Preparation 3 is productive of the corresponding Zea-methylthen dissolved in 15 ml. of methylene chloride, washed with water, dried over sodium sulfate, and concentrated to about 5 ml. Methanol (10 ml.) was then added and the solution was concentrated to 9 ml. The concentrated solution was then treated with 0.15 ml. of 10 percent aqueous sodium hydroxide solution. After cooling, the formed crystals were collected on a filter to give 0.71 g. of 20:- methyl 17a-hydroxy-4,9(1l)-pregnadiene-3,20-dione 17- acetate melting at 241-243 C. Recrystallization from methanol gave 0.65 g. of 2u-methyl-17a-hydroxy'4,9(11)- pregnadiene-3,20-dione 17-acetate melting at 24l-244 C., [a] -|7 5 (chloroform);

v g 1727,1675, 1640 and 1618 01117 In the same manner substituting the anhydride of another hydrocarbon carboxylic acid, e.g., an aliphatic acid, e.g., acetic, propionic, butyric, valeric, hexanoic, lauric, trimethylacetic, isobutyric, isovaleric, tertiary butylacetic, or formic acid (in the presence of acetic anhydride), a cycle-aliphatic acid, e.g., B-cyclopentylpropionic, cyclohexanoecarboxylic, cyclohexylacetic, an alkaryl acid, e.g., benzoic, phenylacetic, S-phenylpropionic, o, m-, p-toluic, a saturated dibasic acid (which can be converted into water soluble, e.g., sodium, salts), e.g., succinic, adipic, a monobasic unsaturated acid, e.g., acrylic, crotonic, undecylenic, propiolic, Z-butynoic, undecolic, cinnamic, dibasic unsaturated acids (which can be converted into water soluble, e.g., sodium, salts), e.g., maleic and citraconic, and the like, for acetic anhydride in the procedure of Preparation 2 is productive of the corresponding 20:- methyl 17a-hydroxy-4,9( 1 l -pregnadiene-3,20-dione l7- acylate, e.g., 2a-methyl-17a-hydroxy-4,9 l l)-pregnadiene- 3,20-dione l7-propionate, Zea-methyl-l7a-hydroxy-4,9- 11 )-pregnadiene-3,20-dione 17-butyrate, 2a-methyl-17 ahydroxy-4,9 1 1 )-pregnadiene-3 ,20-dione 17-caproate, 2ozmethyl l7u-hydroxy-4,9(ll)-pregnadiene-3,20-dione 17- (fi cyclopentylpropionate) 2a methyl-l7a-hydroxy 4,9,- 1(ilgl)-pregnadiene-3,20-dione l7-phenylacetate and the c bromo-l1,8,17a-dihydroxy-4pregnene-3,20-dione 17- acylate, e.g., 2a-methyl-9u-bromo-11B,l7a-dihydroxy-4- pregnene-3,20-dione 17-propionate, 2a-methyl-9u-bromo- 11B,17a-dihydroxy-4-pregnene-3,20-di0ne 17-butyrate, 2amethyl 9a-bromo-11B,17m-dihydroxy-4-pregnene-3,20-dione 17-caproate, 2e-methy1-9a-bromo-1'1B,l7a-dihydroxya 4-pregnenee3,20-dione 17-(fi-cyclopentylpropionate), 2amethyl 9a-bromo-11B,l7a-dihydroxy-4-pregnene-3,20-dione 17-phenylacetate, and the like.

EXAMPLE 1 2m-methyl-9fl,11)S-epoxy-17a-hydroxy-4-pregnene- 3,20-dione 17-acetate A solution of 390 mg. of 2u-methyl-9u-bromo-115,170- dihydroxy-4-pregnene-3,20-dione 17-acetate in 10 ml. of acetonewas heated to reflux overnight with 400 mg. of potassium acetate. The suspension was then diluted with 15 m1. of water which dissolved the inorganic salts and precipitated the epoxide. The solid was collected on a filter, washed withwater and air dried to give 270 mg. of 2a-methyl-9fi,11B-epoxy-l7a-hydroxy-4-pregnene-3,20- dione 17-acetate as fine needles melting at 214-218 C. with decomposition. A sample was recrystallized from acetonezSkellysolve B hexanes to give 2u-methyl-9 3,11fiepoxy-l7a-hydroxy-4-pregnene-3,20-dione 17-acetate melting at 220.0-224.0 C.;

A512? 243 mp. (14,700), 292 mp (128) n max. 1725, 1710, 1670, 1625, 1265, and 1220 cm.-

Analysis.-Calcd. for C H O C, 71.97; H, 8.05. Found: C, 71.87; H, 8.00.

In the same manner substituting another Za-methyl-Qabromo-l15,17adihydroxy-4-pregnene-3,20-dione l7-acylate wherein the acyl radical is that of an acid listed in Preparation 2 above for 2ot-methyl-9a-bromo-11,8,l7a-dihydroxy-4-pregnene-3,20-dione 17 -acetate in the procedure of Example -1 is productive of the corresponding 20:- methyl 9,3,1lfi-epoxy-17a-hydroxy-4-pregnene-3,20-dione 17-acylate, e.g., 2a-methyl-9/3,11B-epoxy-17a-hydroxy-4- pregnene-3,20-dione 17-propionate, 2a-methyl-9B,11;3- epoxy-17rx-hydroxy-4-pregnene-3,20-dione 17-butyrate, 2amethyl 9,8,11fi-epoxy-17a-hydroxy-4-pregnene-3,20-dione 17-caproate, 2a-methyl-9;3,1lfl-epoxy-17a-hydroxy-4-pregnene-3,20-dione 17-(fl-cyclopentylpropionate), 2a-methyl- 9;3,11;8 epoxy 17a. hydroxy-4-pregnene-3,ZO-dione 17- phenylacetate and the like.

EXAMPLE 2 2a methyl 9a fluoro 11,13,170; dihydroxy 4 pregnene-3,20-dione 17-acezate A 200 mg. portion of 2a-methyl-9fi,llfi-epoxy-lh-hydroxy-4-pregnene-3,20-dione 17-acetate dissolved in 10 ml. of methylene chloride and 2 ml. of purified tetrahydrofuran was chilled to Dry-Ice temperature and added to a solution of 1 g. of liquid hydrogen fluoride in 5 ml. of methylene chloride. The reaction was allowed to proceed for a period of about 60 hours at 4 C. The reaction mixture was then poured into 40 ml. of dilute aqueous sodium bicarbonate solution and the product was extracted with methylene chloride. The methylene chloride extract was washed consecutively with dilute aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and then dried over sodium sulfate. The dried methylene chloride solution thus obtained was absorbed onto a short column of Florisil synthetic magnesium silicate and eluted with percent acetone in Skellysolve B hexanes to give a crystalline solid, which was recrystallized from acetone: Skellysolve B hexanes to give 90 mg. of 2a-methyl-9e-fluoro-l1 3,17u-dihydroxy- 4-pregnene3,20-dione 17-acetate melting at 218-200 C. An analytical sample was prepared by two recrystallizations from acetonezSkellysolve B hexanes to give 2amethyl-9a-fluoro 1118,1711 dihydroxy-4pregnene-3,20- dione 17-acetate melting at 226.5 -228.0 C. with decomposition:

Afifli? 237.5 m (15,900), flex 284 m (164) 6 u max. 3440, 1727, 1708, 1666, 1631, 1267, 1250, and 1214 cmr Analysis.-Calcd. for C24H3505FI C, H, 7.91. Found: C, 68.58; H, 7.88.

In the same manner substituting another Za-methyll7a-hydroxy-9fl,l1/3-epoxy-4pregnene-3,20-dione 17-acylate wherein the acyl radical is that of an acid listed in Preparation 2 above, for Zea-methyl-17a-hydroxy-9fl,1lflepoxy-4-pregnene-3,ZO-dione 17-acetate in the procedure of Example 2 is productive of the corresponding 20:- methyl 9a-fiuoro l15,17a-dihydroxy-4-pregnene-3,20 dione 17-acylate, e.g., 2u-methyl-9a-fiuoro-l 113,17oc-dihY- droxy-4-pregnene-3,20-dione 17-propionate, 2oz methylu-fiuoro 11,3,170: dihydroxy-4pregnene-3,20-dione 17- butyrate, 2oz methyl-Qu-fluoro-l1fi,17a-dihydroxy 4- pregnene-3,20-dione 17- caproate, 2a methyl-9a-fluoro- 1l 3,l7oc dihydroxy-4-pregnene-3,20-dione 17-(fi-cyclopentylpropionate), 2a methyl-9afluoro l1B,17a-dihydroxy-4-pregnene-3,20-dione l7 phenylacetate and the like.

We claim:

1. 2a methyl 9a fiuoro-l1p,17a-dihydroxy-4-pregnene-3,20-dione 17-acylate, wherein the acyl radical is that of a hydrocarbon carboxylic acid containing from 1 to 12 carbon atoms, inclusive.

2. 201 methyl 9a fluoro 113,170; dihydroxy 4- pregnene-3,20-dione 17-acetate.

References Cited in the file of this patent UNITED STATES PATENTS 2,852,511 Fried Sept. 16, 1958 2,865,935 Schmeider et al. Dec. 23, 1958 2,892,851 Bergstrom et al. June 30, 1959 

1. 2A - METHYL - 9A - FLUORO-11B,17A-DIHYDROXY-4-PREGNENE-3,20-DIONE 17-ACYLATE, WHEREIN THE ACYL RADICAL IS THAT OF A HYDROCARBON CARBOXYLIC ACID CONTAINING FROM 1 TO 12 CARBON ATOMS, INCLUSIVE. 